title: The role of cardiovascular disease-associated iron overload in Libby amphibole-induced acute pulmonary injury and inflammation.
abstract: Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-overload and oxidative stress. Healthy male Wistar Kyoto (WKY), spontaneously hypertensive (SH) and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25 or 1.0  mg/rat LA and examined at 1 day, 1 week or 1 month. Although histologically it was not possible to distinguish severity differences between strains in LA-induced initial inflammation and later fibrosis, quantitative assessment of biomarkers showed strain-related differences. LA-induced neutrophilic inflammation was reversible in WKY but persisted more in SH and SHHF. Lung MIP-2 mRNA increased only in WKY at 1 day in response to LA but not in SH and SHHF. Bronchoalveolar lavage fluid (BALF) protein increased in SH but not WKY at 1 week and 1 month, while γ-glutamyltransferase and N-acetyl-β-D-glucosaminidase activities increased in all strains (WKY>SH=SHHF). BALF ferritin levels were high at baseline and increased following LA exposure only in SH and SHHF. Ferritin heavy chain mRNA increased only in SHHF at 1 day. At 1 month ferritin light chain mRNA declined from already high baseline levels in SHHF but increased in WKY and SH suggesting its differential involvement in LA-induced injury in Fe-overload. Unlike WKY, both SHHF and SH failed to increase the lung lining antioxidant, ascorbate, in response to LA. We conclude that underlying CVD-associated Fe-overload is likely linked to persistent lung injury, inflammation and antioxidant decompensation following LA exposure in rats.
authors.affiliation: University of North Carolina Chapel Hill, NC, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shannahan
authors.forename: Mette
authors.initials: M
authors.lastname: Schladweiler
authors.forename: Danielle
authors.initials: D
authors.lastname: Padilla-Carlin
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Judy
authors.initials: J
authors.lastname: Richards
authors.forename: Andrew
authors.initials: A
authors.lastname: Ghio
authors.forename: Stephen
authors.initials: S
authors.lastname: Gavett
authors.forename: Urmila
authors.initials: U
authors.lastname: Kodavanti
mesh_terms: D000818:Animals; D017636:Asbestos, Amphibole / Q000008:administration & dosage / Q000633:toxicity*; D001195:Asbestosis / Q000378:metabolism / Q000503:physiopathology*; D001205:Ascorbic Acid / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000503:physiopathology*; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019190:Iron Overload / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000008:administration & dosage / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012720:Severity of Illness Index
chemical_list: D017636:Asbestos, Amphibole; D015415:Biomarkers; D054426:Chemokine CXCL2; C513296:Cxcl2 protein, rat; D052638:Particulate Matter; D012333:RNA, Messenger; D005293:Ferritins; D001205:Ascorbic Acid